Many studies suggest that the ORL- 1 receptor, like the opioid receptor systems, has an important function in modulation and perception of pain signaling. Specific interactions with the ORL-l receptor may result in therapeutically useful agents that lack the side effects that are observed with traditional opiate receptor agonists used in pain management. During our Phase I SBIR grant, we identified two structurally diverse, chemically tractable classes of compounds that are antagonists at the ORL- 1 receptor. This Phase H proposal describes a rational approach to develop the structure-activity relationships for each of these and to determine their therapeutic utility in the treatment of inflammatory and neuropathic pain. Compounds that possess the desired pharmacological profile will be rapidly advanced into preclinical development and clinical evaluation. The nonpeptide antagonists that arise from this project will represent novel therapeutic agents to treat chronic pain states where there is currently no optimal therapy available. In addition, compounds arising from these series will be useful research tools for defining the physiological role and therapeutic relevance of the ORL-I receptor in the treatment of other neurologic or somatic disorders.